Cholinergic Nerve Activity Overview

Cholinergic Nerve Activity

• Action potentials, propagated by voltage-sensitive sodium channels, arrive at nerve endings.
• Voltage-sensitive calcium channels open, increasing intracellular calcium concentration.
• Elevated calcium levels trigger the release of neurotransmitter contents from synaptic vesicles into the synaptic space.
• Botulinum toxin can block this release.
• Certain bacterial toxins cause food poisoning (botulism), inhibiting acetylcholine (ACh) release, leading to skeletal muscle paralysis.
• Botox, a preparation of these toxins, is injected into muscles to temporarily paralyze them for various medical conditions.
• Nicotinic muscle (Nm) receptors are cholinergic receptors at the neuromuscular junction (NMJ) of skeletal muscle.
• Drugs that block ACh effects at the NMJ are neuromuscular blockers or skeletal muscle relaxants.

Clinical Indications for Anticholinesterase Drugs

• Botulinum toxin, derived from Clostridium botulinum, inhibits ACh release from cholinergic nerve endings, causing muscle paralysis.
• Local intradermal injections of botulinum toxin (Botox) can temporarily decrease facial wrinkles.
• Botox, Dysport, and Botulinum toxin type B (Myobloc) are injected intramuscularly to treat muscle disorders (e.g., migraine, spasms).
• Treatments last 1-3 months.

Cholinergic Drugs

• Cholinergic drugs mimic acetylcholine (ACh) effects at cholinergic (muscarinic) receptors. Another similar term is parasympathomimetic.
• Cholinergic drugs are divided into direct-acting and indirect-acting groups.
• Direct-acting drugs bind to cholinergic receptors, producing effects similar to ACh.
• Indirect-acting drugs inhibit the enzyme acetylcholinesterase, increasing ACh concentration and effects at muscarinic and nicotinic receptor sites.

Cholinergic Drugs and Their Major Clinical Indications

• Direct-acting drugs like acetylcholine, bethanechol, carbachol, and pilocarpine are used for specific conditions.
• Indirect-acting drugs (anticholinesterases) like echothiophate, edrophonium, neostigmine, physostigmine, pyridostigmine, donepezil, galantamine, and rivastigmine are used for a range of conditions, including glaucoma, myasthenia gravis, and Alzheimer's disease.

Multiple Choice Questions

• Parasympathetic receptors on internal organs are classified as muscarinic.
• Cholinergic drugs increase gastrointestinal motility.

Muscarinic Agonists ("Cholinergic Drugs")

• Direct-acting cholinergic drugs include choline esters (e.g., acetylcholine, carbachol) and naturally occurring alkaloids (e.g., pilocarpine).
• Indirect-acting drugs are cholinesterase inhibitors, including reversible (e.g., physostigmine, pyridostigmine) and irreversible (e.g., organophosphates) types.

Carbachol (Carbamylcholine)

• Carbachol has both muscarinic and nicotinic actions and is a potent miotic.
• It's used to treat glaucoma by lowering intraocular pressure.
• It has a 4–8-hour duration of action.

Pilocarpine

• Pilocarpine is a strong secretagogue (stimulates secretions like sweat, saliva, and tears).
• It produces rapid miosis and ciliary muscle contraction when applied topically.
• It's the drug of choice for emergency glaucoma treatment.
• Pilocarpine can cause CNS disturbances and poisoning.

Indirectly Acting Cholinergic Agents (Anticholinesterases)

• Anticholinesterases increase acetylcholine (ACh) levels by inhibiting cholinesterase.
• Reversible inhibitors (neostigmine, physostigmine) are therapeutically important.
• Irreversible inhibitors (e.g., organophosphates) are highly toxic insecticides.

Neostigmine

• Neostigmine, a reversible cholinesterase inhibitor, is used in myasthenia gravis, urinary retention treatment, and Alzheimer's disease.
• Muscarinic effects include bradycardia, hypotension, and increased gastrointestinal motility.
• Nicotinic effects include skeletal muscle stimulation at low doses and ganglionic blockade at high doses.
• Adverse effects are cholinergic stimulation (e.g., salivation, abdominal pain).

Myasthenia Gravis

• Myasthenia gravis is a neuromuscular junction disorder causing muscle weakness and fatigue.
• It's due to reduced acetylcholine receptors caused by antibodies.
• Diagnosis uses neostigmine.

Physostigmine (Eserine)

• Physostigmine is a potent cholinesterase inhibitor.
• It readily crosses the blood-brain barrier and affects the CNS at therapeutic doses.
• Used as a miotic and in glaucoma treatment.
• It can cause seizures, bradycardia, and cardiac output depression at high doses.

Edrophonium (Tensilon)

• Edrophonium is a short-acting cholinesterase inhibitor similar to neostigmine.
• It's used to diagnose myasthenia gravis.
• It has rapid onset and short duration of action.

Irreversible Cholinesterase Inhibitors

• Irreversible cholinesterase inhibitors are highly toxic chemicals, often used as pesticides (e.g., organophosphates like serine, parathion, and malathion).
• They inactivate cholinesterase by forming a stable bond, leading to prolonged cholinergic effects.

Actions of Cholinesterase Inhibitors

• Muscle fasciculation, miosis, salivation, sweating, and respiratory distress are common actions.
• Central nervous system (CNS) effects like anxiety, restlessness, and seizures can also occur.
• Neurotoxicity is a long-lasting consequence.

Treatment of Cholinesterase Inhibitor Poisoning

• Remove the toxic agent.
• Administer atropine to counter the muscarinic effects.
• Administer pralidoxime (2-PAM) to regenerate cholinesterase.
• Administer artificial respiration if necessary.